SAFETY AND BETA-HCG + ERYTHROPOIETIN IN ACUTE STROKE

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 中风仍然是人类发病率和死亡率的主要来源。 中风是西方国家的第三大死亡原因，约1/15的死亡归因于中风，并且是全球第二大死亡原因。 大约85%的患者在急性中风后存活，平均寿命为7年。 大多数人留下了严重的残疾1 -3，减少了活动和参与。 中风最常见的是由血栓栓塞性脑动脉闭塞引起的缺血性梗死，因此可以影响脑功能的各个方面。 中风后缺陷的性质和严重程度差异很大。 在脑梗死后的数周至数月内，大多数患者确实在受中风影响的行为方面表现出一些自发性改善4 -6。 然而，这种恢复是高度可变的，通常是不完整的。 因此，中风是美国和许多其他国家成人残疾的主要原因。 目前批准的中风治疗集中在超急性干预（发病后6-8小时内），旨在挽救受威胁的组织。 一系列先前的动物研究表明，在中风后的最初几天内引入神经营养疗法也可以获得行为增益7 -9。 重要的是，这种方法允许以天而不是以小时为单位的干预时间窗口。 使用本文提出的治疗方案的临床前研究也支持用该方法改善结果的潜力。 这种干预被认为是从神经营养机制中获得收益，即，这种干预不会减少梗死体积，而是促进与恢复相关的脑事件10 -17。 越来越多的研究探索了卒中后自发恢复的神经生物学，部分原因是希望利用这些信息制定改善患者结局的策略18 -20。 在中风后的几周内，大脑中出现了许多变化。 这些已经在实验室动物中风的实验模型中在多个水平进行了描述。 在经历实验性单侧梗死的动物中进行的细胞和分子研究已经表征了离子和神经递质变化、皮质兴奋性的变化、炎症、血管生成、神经发生、突触发生和细胞生长，其中许多在单侧损伤后的几天至几周内双侧发展21。 大量证据支持这样的观点，即这些事件中的许多事件有助于人类中风后功能的自发恢复，too 17，18，22-26。 此外，已经发现，在中风的实验动物模型中，外源性干预放大了这些分子事件，同时改善了行为结果。 例子包括安非他明12、生长因子8、27、细胞疗法28、29、大脑刺激30 -32、环境复杂性增加33、34和身体活动水平增加10。 因此，在梗塞后的几天内出现离散的分子脑事件，这些脑事件可能是自发恢复的基础或基本上有助于自发恢复，并且在动物中，这些事件可以在治疗上与改善的行为结果相关联地增强。 这些事件是当前治疗干预的目标，其安全性将在拟定研究中进行评估。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Stroke remains a major source of human morbidity and mortality. Stroke is the third leading cause of death in the Western countries, with approximately 1 in 15 deaths attributable to stroke, and the second leading cause of death worldwide. Approximately 85% of patients survive an acute stroke, living an average of seven years thereafter. Most are left with significant disability1-3, which reduces activities and participation. Stroke most frequently is caused by an ischemic infarct due to thromboembolic cerebral artery occlusion and, thus, can affect all aspects of brain function. The nature and severity of post-stroke deficits vary widely. Over the weeks-months following a brain infarction, most patients do show some spontaneous improvement in those behaviors affected by stroke4-6. However, this recovery is highly variable and generally incomplete. As a result, stroke is the leading cause of adult disability in the U.S. and many other countries. Currently approved stroke therapies are focused on hyperacute interventions (within 6-8 hours after onset) and aim to salvage threatened tissue. A range of prior animal studies suggest that behavioral gains can also be achieved by introducing a neurotrophic therapy within the first few days after stroke7-9. Importantly, such an approach allows a time window for intervention that is measured in days rather than hours. Preclinical studies using the therapeutic regimen proposed herein also support the potential to improve outcome with this approach. Such interventions are thought to derive gains from a neurotrophic mechanism, i.e., the intervention does not reduce the volume of infarct, but instead promotes recovery-related brain events10-17. Increasing investigation has explored the neurobiology of spontaneous post-stroke recovery in part because of the hope to use this information to develop strategies to improve patient outcomes18-20. A number of changes arise in the brain over the weeks following a stroke. These have been described at multiple levels in experimental models of stroke in laboratory animals. Cellular and molecular studies in animals undergoing an experimental unilateral infarct have characterized ion and neurotransmitter changes, changes in cortical excitability, inflammation, angiogenesis, neurogenesis, synaptogenesis, and cellular growth, many of which evolve bilaterally, during the days to weeks that follow a unilateral insult21. A body of evidence supports the idea that many of these events contribute to spontaneous recovery of function after a stroke in humans, too17, 18, 22-26. Furthermore, exogenous interventions have been found that in experimental animal models of stroke amplify these molecular events and simultaneously improve behavioral outcome. Examples include amphetamine12, growth factors8, 27, cellular therapies28, 29, brain stimulation30-32, increased environmental complexity33, 34, and increased physical activity level10. Thus, there are discrete molecular brain events that arise in the days following an infarct, these brain events likely underlie or substantially contribute to spontaneous recovery, and in animals these events can be therapeutically augmented in association with improved behavioral outcome. These events are the target of the current therapeutic intervention whose safety will be assessed in the proposed study.